What is the current understanding of treatment options in therapy resistant depression?/nBackground

Fråga: What is the current understanding of treatment options in therapy resistant depression?

Background: A 61-year-old male patient has suffered from depression for approximately two years. He has also psoriasis, and Parkinson´s disease was recently diagnosed. Different drugs like citalopram, moclobemide, amitriptyline (+ flupenthixol) have been tried with little benefit. Electroconvulsive therapy (ECT) achieved some transient improvement. Now the patient is treated with citalopram and levodopa. Also lithium was tried; however, because his psoriasis worsened, it had to be withdrawn.

Sammanfattning: Therapy resistant depression constitutes a significant clinical problem. Several treatment options are available, but possible TCA-resistance should first be confirmed by measuring drug concentrations in plasma. Continued research in therapy resistant depression is needed.

Svar: Therapy resistant depression constitutes a significant clinical problem. The situation in Sweden has been summarized in a Medical Product Agency (Läkemedelsverket) workshop published in 1992 (1). Only a brief summary of current understanding and some general guidelines are presented here. The heterogeneity of depression, diagnostic problems and the possible different biological subtypes are outside the scope of this summary.

The response rate to tricyclic antidepressants (TCA) is at best 70-80 per cent. In clinical practice, however, the effectiveness is often much less. This is due to the fact that doses employed are often too low and not individualized. Ultrarapid metabolism of drugs due to CYP2D6 (a P450 isoform) gene amplification constitutes one possibility for therapeutic failure after standard dosage (2). Patient non-compliance is, however, probably a more common reason for therapeutic failure (3). Therefore, it should be recognized that TCA-resistance should be confirmed with an adequate determinations of drug plasma concentration. It should also be mentioned that in a recent study, though non-randomized, the response rate in elderly in-patients with major depression was 67 per cent in nortriptyline treated patients compared with only 23 per cent in the fluoxetine group (4). Nortriptyline dosage was individualized using therapeutic drug monitoring (TDM).

ECT is commonly recommended as second line treatment of depression. The following pharmacological treatments were suggested by the Swedish expert group in patients resistant to TCAs (5): Intravenous treatment with clomipramine, first generation (non-selective) MAO inhibitors (available only under special license), mianserin and lithium, especially in combination with a tricyclic antidepressant. The addition of small doses of thyroxine may also be beneficial, especially in the presence of subclinical hypothyroidism.

Other treatment options which are not well documented that have to be considered experimental include: addition of L-tryptophan to TCA-therapy, a combination of a TCA and a MAO inhibitor, and a combination of mianserin and lithium. Too, a plethora of other "cocktails" have also been suggested (6).

Lithium may indeed cause an exacerbation of psoriasis (7). 1 Thelander S: Therapy resistant depression. In Workshop on Treatment of Depression. Uppsala. 1992, pages 263-269 (enclosed) 2 Bertilsson L, Dahl M-L, Sjöqvist F, Åberg-Wistedt A, Humble M, Johansson I, Lundqvist E, Ingelman-Sundberg M: Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine. Lancet 1993; 341: 63 3 Isacsson G: Depression, antidepressants and suicide. A study of the role of antidepressants in the prevention of suicide. Academic dissertation, Stockholm 1994 4 Roose SP, Glassman AH, Attia E, Woodring S: Comparative efficacy of the selective serotonin reuptake inhibitors and the tricyclics in the treatment of melancholia. Am J Psychiatry 1994; 151: 1735-1739 5 Treatment of depression. Recommendations from the group. In Workshop on Treatment of Depression. Uppsala. 1992, pages 297-310 (enclosed) 6 Nierenberg AA, White K: What next? A review of pharmacologic strategies for treatment resistant depression. Psychopharmacol Bull 1990; 26: 429-460 (enclosed) 7 Dollery, Therapeutic drugs. 1992; Vol 2: page L47-52